A Genetic Study of Susceptibility to Experimental Tuberculosis in Mice Infected With Mammalian Tubercle Bacilli

Abstract

A study has been made of the genetic aspects of the difference between two inbred strains of mice (C57B1/6 and Swiss) in response to experimental infection with mammalian tubercle bacilli. Males and females, 4 to 6 weeks of age were inoculated intravenously with 0.2 ml of a 1/50 culture dilution of Mycobacterium tuberculosis var. bovis (Vallée strain) grown in tween albumin medium. Mean survival time for C57B1 animals was 28.1 ± 0.6 days and for Swiss, 55.3 ± 0.6 days postinfection. The characteristic survival time of the two strains was reversed in mice receiving a smaller infective dose. The age of mice at the time of inoculation also affected the results of infection: both C57B1 and Swiss, inoculated at 12 months of age, died at the same rate, but when inoculated at older ages, C57B1 survived slightly longer. Bacteriologic studies demonstrated that there was no significant difference between the two mouse strains with regard to the numbers of viable units of tubercle bacilli recovered from various organs during the 2 week period following infection with a 10–3 culture dilution of Vallée. Moreover, the standard infective inoculum (1/50 culture dilution) did not activate corynebacterial pseudotuberculosis in C57B1 mice, a strain known to be latently infected with Corynebacterium kutscheri, rapid multiplication of tubercle bacilli occurred, but no corynebacteria were recovered. When C57B1 and Swiss strains were crossed, survival tests after infection with the standard inoculum demonstrated that mice of the F1 generation were more resistant than either parent. Whether the overdominance was due to a new combination of parental genes for resistance or to heterosis was not determined. The increased litter size of the F1 mice, an evidence of increased vigor, supports the view that heterosis was involved. In backcrosses to the resistant strain (Swiss), survival time gradually became stabilized at approximately the parental level. In the 1st backcross to the susceptible strain (C57B1), survival times fell into two classes indicating segregation of genes, with perhaps dominance of genes from the Swiss. After repeated backcrosses to C57B1, mice of the 4th backcross generation had a survival time essentially the same as that of the original parental strain. On the basis of having obtained progeny characterized by the original parental susceptibilities after genetic tendencies had been intermingled by crossbreeding, it was concluded that hereditary factors influenced the response of mice to experimental infection with M. tuberculosis. The number of genes was not determined.

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

“…At high power (i), some of the epithelioid macrophages can be seen to contain acidfast bacilli (arrows). 374,213,156,19,181,415,493,218,196,265,396,425,D11Mit226,19,20,349,194,39,67,224,103 109,145,206,541,150,361,221,209 D12Mit12,153,34,14,118,233,20 D2Mit1,32,367,61,91,436,164,401,225,311,200 D13Mit271,60,139,250,145,293,35 D3Mit176,306,69,241,51,72,156,106,17,128 D14Mit207, …”

“…Differences in susceptibility to tuberculosis have been noted over the past 50 years in a variety of inbred and outbred mouse strains, using different M. tuberculosis isolates, different infection routes and doses, and different evaluations of susceptibility. [12][13][14][15][16] When studied, genetic control of susceptibility appeared multigenic, 14 including a recent study that suggested six chromosomal regions contributing to the reported difference between the A/Sn and I/St strains in M. tuberculosis infection-induced body weight loss. 17 Although a role for H-2 genes in genetic susceptibility (H-2k protective over H-2b) has been identified, 18,19 additional genes have yet to be identified.…”

The family history: the first genetic test, and still useful after all those years?

“…Karl Pearson in 1908 suggested that familial clustering of tuberculosis might represent common, innate susceptibility to the tubercle bacillus, 17 a notion that received experimental support a half-century later by eminent microbiologist René Dubos. 18 As public health measures (cleaning the air to permit sun exposure, fortifying milk with vitamin D, and table salt with iodide) were successful in reducing the prevalences of some disorders, the causes of the remaining cases were more likely to be genetic. 19 Many physicians practicing today relied, in part, on textbooks to ingrain the components of the clinical evaluation.…”

Corynebacterium kutscheriand its alleged avirulent variant in mice

“…1964) that cortisone evoked the clinical disease in mice given the alleged variant? We suggest that C. kutscheri, which is an insidious infiltrator into mouse colonies even under the best regulated circumstances, may have established itself unbeknown into mouse colonies other than those already heavily infected Lynch et al 1965; Pierce-Chase et al 1964). Such a possibility could have accounted for the results of the preliminary experiments reported by Fauve et al (1964) before the use of geneticallymarked streptomycin-resistant organisms.…”

“…Lynch, Rockefeller University, in 1969. The maintenance of these mice is fully described elsewhere (Lynch et al 1965). …”